This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tuberculosis (TB) kills 2 million people every year 4, 5, and TB is the leading cause of death in people with HIV 5-8. Unfortunately, the current TB vaccine, bacille Calmette-Gu[unreadable]rin (BCG), fails to prevent innumerable cases of TB in people with HIV. Therefore, the identification of a novel TB vaccine is a leading public health priority. The DarDar Trial has now shown that whole inactivated M. vaccae (MV), a novel TB booster vaccine, protects HIV-infected and BCG-immunized adults with CD4 counts = 200 cells/ul from TB. As the first identification of an effective vaccine against TB in over 80 years, this is a major public health advance. However, the immunological mechanisms through which MV prevents TB disease in HIV-infected individuals are not known. In fact, the nature of the protective immune response against TB is itself incompletely understood. We hypothesize that Th-type polyfunctional T cell responses to mycobacterial antigens will confer protection against MV, either when induced by MV or generated spontaneously. To test this hypothesis, we will use the extensive prospective clinical outcomes data and a wealth of immunological findings obtained through the DarDar Trial to address the following specific aims: Specific Aim 1: To delineate the immunological mechanisms of MV-induced immune protection from TB in HIV-infected adults, and Specific Aim 2: To characterize the immunological mechanisms of immune protection from TB in HIV-infected adults. The immunological studies conducted through the DarDar Trial offer an unprecedented opportunity to tackle critical questions in TB vaccine science, and to test the hypothesis that Th1-type polyfunctional T cell immune responses contribute to protection from TB. Thus, the studies proposed in this application will contribute substantially to our understanding of how the immune system prevents TB.